@article {292, title = {13,13-Dimethyl-des-C,D analogues of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D$_{3}$ (2MD): total synthesis, docking to the VDR, and biological evaluation}, journal = {Bioorganic \& Medicinal Chemistry}, volume = {19}, year = {2011}, month = {2011 Dec 1}, pages = {7205-20}, abstract = {As a continuation of our studies focused on the vitamin D compounds lacking the C,D-hydrindane system, 13,13-dimethyl-des-C,D analogues of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D(3) (2, 2MD) were prepared by total synthesis. The known cyclohexanone 30, a precursor of the desired A-ring phosphine oxide 11, was synthesized starting with the keto acetal 13, whereas the aldehyde 12, constituting an acyclic {\textquoteright}upper{\textquoteright} building block, was obtained from the isomeric esters 34, prepared previously in our laboratory. The commercial 1,4-cyclohexanedione monoethylene ketal (13) was enantioselectively α-hydroxylated utilizing the α-aminoxylation process catalyzed by l-proline, and the introduced hydroxy group was protected as a TBS, TPDPS, and SEM ether. Then the keto group in the obtained compounds 15-17 was methylenated and the allylic hydroxylation was performed with selenium dioxide and pyridine N-oxide. After separation of the isomers, the newly introduced hydroxy group was protected and the ketal group hydrolyzed to yield the corresponding protected (3R,5R)-3,5-dihydroxycyclohexanones 30-32. The esters 34, starting compounds for the C,D-fragment 12, were first α-methylated, then reduced and the resulted primary alcohols 36 were deoxygenated using the Barton-McCombie protocol. Primary hydroxy group in the obtained diether 38 was deprotected and oxidized to furnish the aldehyde 12. The Wittig-Horner coupling of the latter with the anion of the phosphine oxide 11, followed by hydroxyl deprotection furnished two isomeric 13,13-dimethyl-des-C,D analogues of 2MD (compounds 10 and 42) differing in configuration of their 7,8-double bond. Pure vitamin D analogues were isolated by HPLC and their biological activity was examined. The in vitro tests indicated that, compared to the analogue 7, unsubstituted at C-13, the synthesized vitamin D analogue 10 showed markedly improved VDR binding ability, significantly enhanced HL-60 differentiation activity as well as increased transcriptional potency. Docking simulations provided a rational explanation for the observed binding affinity of these ligands to the VDR. Biological in vivo tests proved that des-C,D compound 10 retained some intestinal activity. Its geometrical isomer 42 was devoid of any biological activity.}, keywords = {Animals, Calcitriol, Cell Differentiation, Crystallography, X-Ray, HL-60 Cells, Humans, Male, Models, Molecular, Molecular Conformation, Rats, Receptors, Calcitriol, Structure-Activity Relationship}, issn = {1464-3391}, doi = {10.1016/j.bmc.2011.09.048}, author = {Katarzyna Plonska-Ocypa and Izabela Sibilska and Rafal R. Sicinski and Wanda Sicinska and Lori A. Plum and Hector F. DeLuca} } @article {299, title = {2-Methylene analogs of 1alpha-hydroxy-19-norvitamin D3: synthesis, biological activities and docking to the ligand binding domain of the rat vitamin D receptor}, journal = {The Journal of Steroid Biochemistry and Molecular Biology}, volume = {89-90}, year = {2004}, month = {2004 May}, pages = {13-7}, abstract = {In continuing efforts towards the synthesis of biologically active vitamin D compounds of potential therapeutic value, new 2-methylene-1alpha-hydroxy-19-norvitamin D(3) analogs 3 and 4 with modified alkyl side chains have been synthesized. The key synthetic step involved Lythgoe-type Wittig-Horner coupling of Windaus-Grundmann type ketones 9, possessing different 17beta-alkyl substituents, with the phosphine oxide 10 prepared from (-)-quinic acid. The prepared vitamins 3 and 4 were ca. eight times less potent than 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) (1) in binding to the rat intestinal vitamin D receptor (VDR). In comparison with the hormone 1 they exhibited slightly lower cellular HL-60 differentiation activity. When tested in vivo; the analog 3 was characterized by very high bone calcium mobilizing potency and intestinal calcium transport activity. Unexpectedly, the 25-methyl compound 4 showed marked calcemic activity in both assays. Computational docking of the vitamin 3 into the binding pocket of the rat vitamin D receptor is also reported.}, keywords = {Animals, Binding Sites, Calcitriol, Female, HL-60 Cells, Humans, Hydrocarbons, Ligands, Methane, Mice, Models, Molecular, Rats, Receptors, Calcitriol}, issn = {0960-0760}, doi = {10.1016/j.jsbmb.2004.03.103}, author = {Pawel Grzywacz and Lori A. Plum and Wanda Sicinska and Rafal R. Sicinski and Jean M. Prahl and Hector F. DeLuca} } @article {298, title = {Model of three-dimensional structure of VDR bound with Vitamin D3 analogs substituted at carbon-2}, journal = {The Journal of Steroid Biochemistry and Molecular Biology}, volume = {89-90}, year = {2004}, month = {2004 May}, pages = {107-10}, abstract = {All Vitamin D analogs possessing the A ring modified at C-2 and showing calcemic activities nest themselves in the VDR binding pocket, oriented towards Tyr 143. Such topology resembles the position of the Vitamin D hormone in hVDRmt [Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 5491]. Conversely, inactive 2beta-methyl-19-nor-analogs anchor the receptor cavity in a distinguishably different manner, namely by their side chain. Moreover, these inactive vitamins have a different conformation around C(6)-C(7) bond. Topology of modeled complexes suggests that a Vitamin D analog will be biologically active if its intercyclic 5,7-diene moiety assumes parallel position to tryptophan aromatic rings; such orientation allows for creating pi-pi interactions. The broad comparison of calcemic activities of the analogs, and their interactions with VDR, revealed that specific hydrophobic contacts are involved in bone calcium mobilization (BCM). These contacts occur between 21-methyl group and a few amino acids (V296, L305 and L309), conserved in the nuclear receptor superfamily. In the inactive 2beta-methyl-19-nor analogs such contacts do not exist. We speculate that two hydrophobic receptor patches, being in close contact with ligand methyl groups, might influence interaction with co-modulators involved in calcium homeostasis.}, keywords = {Animals, Calcium, Carbon, Cholecalciferol, Ligands, Models, Molecular, Molecular Conformation, Rats, Receptors, Calcitriol}, issn = {0960-0760}, doi = {10.1016/j.jsbmb.2004.03.102}, author = {Wanda Sicinska and Piotr Rotkiewicz and Hector F. DeLuca} } @article {290, title = {2-Ethyl and 2-ethylidene analogues of 1alpha,25-dihydroxy-19-norvitamin D(3): synthesis, conformational analysis, biological activities, and docking to the modeled rVDR ligand binding domain.}, journal = {Journal of Medicinal Chemistry}, volume = {45}, year = {2002}, month = {2002 Aug 1}, pages = {3366-80}, abstract = {Novel 19-nor analogues of 1alpha,25-dihydroxyvitamin D(3) were prepared and substituted at C-2 with an ethylidene group. The synthetic pathway was via Wittig-Horner coupling of the corresponding A-ring phosphine oxides with the protected 25-hydroxy Grundmann{\textquoteright}s ketones. Selective catalytic hydrogenation of 2-ethylidene analogues provided the 2alpha- and 2beta-ethyl compounds. The 2-ethylidene-19-nor compounds with a methyl group from the ethylidene moiety in a trans relationship to the C(6)-C(7) bond (E-isomers) were more potent than the corresponding Z-isomers and the natural hormone in binding to the vitamin D receptor. Both geometrical isomers (E and Z) of (20S)-2-ethylidene-19-norvitamin D(3) and both 2alpha-ethyl-19-norvitamins (in the 20R- and 20S-series) have much higher HL-60 differentiation activity than does 1alpha,25-(OH)(2)D(3). Both E-isomers (20R and 20S) of 2-ethylidene vitamins are characterized by very high calcemic activity in rats. The three-dimensional structure model of the rat vitamin D receptor and the computational docking of four synthesized (20R)-19-norvitamin D(3) analogues into its binding pocket are also reported.}, keywords = {Animals, Binding Sites, Biological Transport, Calcitriol, Calcium, Cell Differentiation, Chromatography, High Pressure Liquid, HL-60 Cells, Humans, Intestinal Mucosa, Ligands, Magnetic Resonance Spectroscopy, Male, Models, Molecular, Molecular Conformation, Rats, Receptors, Calcitriol, Spectrophotometry, Ultraviolet, Structure-Activity Relationship, Swine}, issn = {0022-2623}, author = {Rafal R. Sicinski and Piotr Rotkiewicz and Andrzej Koli{\'n}ski and Wanda Sicinska and Jean M. Prahl and Connie M. Smith and Hector F. DeLuca} }